PROJECT SUMMARY Diabetes afflicts approximately 29 million adult Americans (9.3% of the total population), 90-95% of whom have type 2 diabetes (T2D). T2D is a complex disease with both genetic and environmental components and ultimately manifests when pancreatic islets fail to secrete sufficient insulin to compensate for increased insulin resistance. Despite the success of genome-wide association studies (GWAS) in linking >100 loci to islet dysfunction and T2D, we still lack the mechanistic insights necessary to develop novel treatments and preventions. Detailed molecular and phenotypic analyses of each T2D-associated GWAS locus are thus essential to determine how they contribute to islet dysfunction and diabetes. We have recently linked altered C2CD4A/B expression to genetic risk of islet dysfunction and T2D. Our overall objective is to understand the islet/beta cell regulation and function of the C2CD4A/B locus in physiologic and diabetogenic states. We hypothesize that these genes regulate stimulus-secretion coupling and that chronic activation of C2CD4A/B by genetic and/or environmental risk factors contributes to the declines in first-phase insulin secretion that are hallmarks of the early stages of T2D. To test this hypothesis, we will determine the regulatory circuitry controlling C2CD4A/B responses to inflammatory stressors and determine the effect of T2D-associated GWAS variants on C2CD4A/B activity (Aim 1). In parallel, we will dissect the beta cell functions of C2CD4A and C2CD4B in glucose-stimulated insulin secretion (Aim 2). Finally, we will assess the in vivo effects of deleting these genes in a polygenic T2D mouse model (Aim 3). Together, these aims will provide fundamental, mechanistic insights into the regulation and function of the C2CD4A/B locus and will delineate the roles of these genes in islet function and T2D pathogenesis. More broadly, we anticipate the study of this locus will provide new perspectives/insights into the mechanics of insulin secretion and beta cell compensation. The cellular and mouse models that we will create to dissect the regulation and function of the C2CD4A/B locus in diabetes pathogenesis will empower future analyses of novel therapeutic molecules and approaches to target this locus to prevent and treat diabetes.